SALL4 inhibitor SH6 is a small molecule inhibitor of transcription factor SALL4 ZFC4 domain, selectively targets SALL4-expressing cancer cells (EC50=0.5 uM, SNU398 cells), degrades SALL4 protein through the CUL4A/CRBN pathway.
SH6 targets SALL4 via a novel ZFC4 pocket domain.
SH6 displayed greater potencies against SALL4 expressing cancer cell lines H661, H838, and CAL51 (EC50 = 0.21 μM, 1.30 μM, and 0.54 μM, respectively) as compared to SALL4 low cell lines H552 and H2030 (EC50 = 48.4 μM, and 41.6 μM, respectively).
SH6 selectively kills SALL4 expressing liver cancer cells with EC50 values of 0.3 μM to 1.3 μM, but not non-transformed liver cell lines THLE-2 and THLE-3.
SH6 degrades SALL4B through the CUL4A-CRBN pathway, but failed to degrade SALL4B in the absence of ZFC4.
SH6 (20-40 mg/kg) significantly reduced tumor growth in mice with tumors derived from human cancer patients.